The body can engage in blood clotting through the “extrinsic pathway” and the “intrinsic pathway.” Clotting factors mediate the clotting response in both pathways. Both pathways are activated by different stimuli and ultimately feed into a common machinery. In the extrinsic pathway, when vascular injury occurs, a subendothelial cell-surface glycoprotein called “Tissue Factor” (TF) (also known as Factor III) is released at the site of injury triggering blood coagulation in healthy individuals. Tissue factor is found on the outside of blood vessels—normally not exposed to the bloodstream.
Coagulation is mainly triggered by FVIIa activating FX after exposure of TF at the broken vessel wall. Approximately one percent of FVII is circulating in its activated enzyme form (FVIIa). FVIIa forms the so-called “extrinsic tenase” complex with TF leading to activation of factor X to FXa, which leads to activation of initial levels of thrombin, and to activation of FIX to FIXa. Thrombin is required to activate FVIII, FV, and platelets. Formation of the “intrinsic tenase” complex consisting of FIXa and FVIIIa leads to activation of FX at a rate which is several orders of magnitude higher than by the FVIIa/TF complex. These amounts of FXa are required to cause the “thrombin burst” leading to formation of enough fibrin to form a stable blood clot. All these processes occur on the membrane surfaces of activated platelets.
Platelets are anucleic cells that circulate in the blood of mammals. In the absence of trauma, the inner surface of blood vessels is lined with a thin layer of endothelial cells that acts to inhibit platelet activation. When blood vessels are damaged, fibrils of collagen in the extracellular matrix (ECM) are exposed. Platelets then begin to adhere to the collagen through the action of specific receptors for collagen present on their plasma membrane. These adhesions activate the platelets in addition to the earlier described mechanisms. Platelets are also activated by thrombin after initiation of coagulation.
Hemophilia refers to a group of bleeding disorders in which it takes a long time for the blood to clot. Hemophilia A is the most common form of the disorder and is caused by a deficiency in Factor VIII. Hemophilia B is less frequent and is caused by a deficiency in Factor IX. Both forms of hemophilia can be effectively treated by administration of either recombinant or plasma derived FVIII or FIX concentrates. Treatment of hemophilia is complicated by the development of inhibitory antibodies to factors VIII or IX. In the case of Factor VIII (FVIII), inhibitors develop in ˜30% of the patients. Currently approved therapies in these cases include the infusion of plasma-derived prothrombin complex concentrates, like FEIBA, or recombinant Factor VIIa (rFVIIa), as the therapies for acute bleeds.